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New Mechanism Discovered for DNA Recombination and Repair

12.09.2007

A biochemistry research team led by Dr. Andrew H.-J. Wang and Dr. Ting-Fang Wang at the Institute of Biological Chemistry, Academia Sinica(IBCAS), has discovered that the RecA family recombinases function as a new type of rotary motor proteins to repair DNA damages.

The team has recently published two structural biology articles related to RecA family recombinases. One paper is to be published in the online, open-access journal PLoS ONE on September 12, 2007 and the other has been already published in the Nucleic Acids Research on Feb. 28, 2007.

Homologous recombination (HR) is a mechanism that repairs damaged DNA with perfect accuracy, it utilizes the homologous sequence from a partner DNA as a template. This process involves the bringing together of 2 DNA molecules, a search for homologous sequences, and exchange of DNA strands.

RecA family proteins are the central recombinases for HR. The family includes prokaryotic RecA, archaeal RadA, and eukaryotic Rad51 and Dmc1. They have important roles in cell proliferation, genome maintenance, and genetic diversity, particularly in higher eukaryotes. For example, Rad51-deficient vertebrate cells accumulate chromosomal breaks before death. Rad51 and its meiosis-specific homolog, Dmc1, are also indispensable for meiosis, a specialized cell cycle for production of gametes. Mammalian Rad51 and Dmc1 proteins are known to interact with tumor suppressor proteins such as BRCA2.

Since scientists discovered RecA family proteins, it has been assumed that RecA (and other homologs) forms only 61 right-handed filaments (six protein monomers per helical turn), and then hydrolyzes ATP to promote HR and recombinational DNA repair. Whereas a controversial puzzle came out, how the energy of ATP facilitating DNA rotation during the strand exchange reaction.

By X-ray crystallography and atomic force microscopy approaches, Dr. Wangs’ team provided the answer. They reported that archaeal Sulfolobus solfataricus RadA proteins can also self-polymerize into a 31 right-handed filament with 3 monomers per helical turn (reported in PLoS ONE) and a 43 right-handed helical filament with 4 monomers per helical turn (reported in Nucleic Acids Research).

Additional biophysical and biochemical analyses revealed that RecA family proteins may couple ATP binding and hydrolysis to the DNA strand exchange reaction in a manner that promotes clockwise axial rotation of nucleoprotein filaments. Specially, the 61 RadA helical filament undergoes clockwise axial rotation in 2 discrete 120° steps to the 31 extended right-handed filament and then to the 43 left-handed filament. As a result, all the DNA-binding motifs (denoted L1, L2 and HhH) in the RadA proteins move concurrently to mediate DNA binding, homology pairing, and strand exchange, respectively. Therefore, the energy of ATP is used to rotate not only DNA substrates but also the RecA family protein filaments.

This new model is in contrast to all current hypotheses, which overlooks the fact that RecA family proteins are flexible enough to form both right-handed and left-handed helical filaments. From this perspective, these researchers in Taiwan have opened a new avenue for understanding the molecular mechanisms of RecA family proteins.

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